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Malignant Hyperthermia Registry and Genetic Testing

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ClinicalTrials.gov Identifier: NCT02964481
Recruitment Status : Recruiting
First Posted : November 16, 2016
Last Update Posted : February 1, 2019
Sponsor:
Information provided by (Responsible Party):
Children's Hospital Medical Center, Cincinnati

Brief Summary:
The purpose of this study is to to determine the penetrance of known and probable pathogenic variants in genes and the factors that contribute to penetrance in a population of children and adults in the United States exposed to Malignant Hyperthermia (MH) trigger agents.

Condition or disease
Malignant Hyperthermia

Detailed Description:
The purpose of the study is to determine how genetic mutations and variants in combination with non-genetic factors influence risk for MH in children who had general anesthesia with triggering agents and develop reliable predictive MH risk algorithms. Rationale: Once the factors responsible for MH risk are determined, it will be possible to better predict risk and develop better individualization of anesthetics such as tailored selection of intravenous anesthetics, regional anesthesia and avoidance of all triggering agents. The long-term goal is to tailor and improve safety of anesthetic and clinical care and to reduce mortality, morbidity and cost of care due to MH with right anesthetics and muscle relaxants for endotracheal intubations for an individual child.

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Study Type : Observational
Estimated Enrollment : 130 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Donation of Blood for Genetic Testing With Clinical Data From the North American Malignant Hyperthermia Registry
Study Start Date : August 2015
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : August 2020

Resource links provided by the National Library of Medicine


Group/Cohort
Malignant Hyperthermia Phenotype cases
Samples from persons who identify as having the malignant hyperthermia phenotype by the North American MH Registry (NAMHR)
Caffeine Halothane Contracture Test negative controls
Controls who had negative Caffeine Halothane Contracture Test (CHCT) from North American MH Registry (NAMHR)



Primary Outcome Measures :
  1. Genetic comparison of MH phenotype subjects to that of the CHCT negative control subjects. [ Time Frame: Within data collection period (5 years total). ]
    MHS subjects and CHCT negative controls recruited from the North American MH Registry will have whole genome sequencing


Secondary Outcome Measures :
  1. Genomic and demographic factors that influence Malignant Hyperthermia. [ Time Frame: Within data collection period (5 years total). ]
    A diagnostic predictive algorithm based on multiple genetic and other risk factors assessed from DNA data collected on NAMHR subjects and CCHMC subjects will be used to differentiate MH influences.

  2. Isolate DNA from blood samples to obtain information [ Time Frame: Within data collection period (5 years total). ]
    Blood samples will be used to obtain DNA methylation information by measuring CpG sites in important genes (RYR1, CACNA1S, STAC3 and other MH relevant genes) and/or use of the MethylationEPIC array.

  3. Induced pluripotent stem cells will be used for functional testing and gene editing [ Time Frame: Within data collection period (5 years total). ]
    Induced pluripotent stem cells will be differentiated into skeletal muscle cells and functional testing of the ryanodine receptor will be performed. In addition, gene editing using CRISPR technology will be performed to edit/delete variants of uncertain significance.

  4. Differences in expression of MH related genes will be assessed by RNA sequencing [ Time Frame: Within data collection period (5 years total). ]
    RYR1 (and other MH related genes) in MH phenotype cases and controls will be assessed by RNA sequencing.


Biospecimen Retention:   Samples With DNA
Blood samples will be used to extract DNA for genotyping, pyrosequencing and pluripotent stem cells.


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Patients with documented MH clinical presentation and CHCT negative controls from NAMHR
Criteria

Inclusion Criteria:

  • Any English speaking person registered at NAHMR who has had a positive clinical manifestation of Malignant Hyperthermia
  • Any person with a positive Caffeine Halothane Contracture probTest (CHCT) or a close relative of a person that had these.

Exclusion Criteria:

  • Any person who has NOT had a positive clinical manifestation of Malignant Hyperthermia
  • Any person with a positive Caffeine Halothane Contracture Test (CHCT) or NOT a close relative of a person that had these. Non-English speaking registrants will be excluded.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02964481


Contacts
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Contact: John McAuliffe, MD (513)636-8535 John.McAuliffe@cchmc.org
Contact: Kristi Barnett (513) 636-5983 Kristi.barnett@cchmc.org

Locations
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United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: John McAuliffe, MD    513-636-8535    John.Mcauliffe@cchmc.org   
Contact: Kristi Barnett    5136365983    kristi.barnett@cchmc.org   
Principal Investigator: John McAuliffe, MD         
Sponsors and Collaborators
Children's Hospital Medical Center, Cincinnati

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Responsible Party: Children's Hospital Medical Center, Cincinnati
ClinicalTrials.gov Identifier: NCT02964481     History of Changes
Other Study ID Numbers: 2015-1749
First Posted: November 16, 2016    Key Record Dates
Last Update Posted: February 1, 2019
Last Verified: January 2019

Keywords provided by Children's Hospital Medical Center, Cincinnati:
malignant
genetics
RYR1
CAC-NA1S
hyperthermia

Additional relevant MeSH terms:
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Fever
Malignant Hyperthermia
Body Temperature Changes
Signs and Symptoms
Intraoperative Complications
Pathologic Processes
Postoperative Complications